Anti-HIV infection agents and method for treating HIV infection

ABSTRACT

The present invention relates to agents for anti-HIV infection, which contain, as an active ingredient, at least one photosensitizing dye selected from the group consisting of the compounds of the formulae (I) and (II):                    
     wherein R 1 , R 2  and R 3  are the same or different and each represents alkyl group having 1 to 4 carbon atoms, R 4 , R 5  and R 6  are the same or different and each represents alkyl group having 5 to 10 carbon atoms, and X −  represents a physiologically acceptable monovalent anion. The present invention also relates to a method for treating or preventing HIV infection diseases, which includes administering the photosensitizing dye. A daily dose of the photosensitizing dye is usually 2 to 100 μg, and preferably 5 to 40 μg, per kg body weight. Administration of the photosensitizing dye to HIV infected subjects leads to improvement or cure of the symptoms of AIDS related complex and increase in CD4-positive lymphocytes, which is effective for the treatment of HIV infection diseases.

This is a 371 of application PCT/JP98/05925 filed Dec. 24, 1993.

TECHNICAL FIELD

The present invention relates to a medicament useful for treating andpreventing HIV infection diseases, and a method for treating orpreventing HIV infection diseases. More particularly, the presentinvention relates to an agent for anti-HIV infection, comprising aphotosensitizing dye as an active ingredient. The present invention alsorelates to a method for treating or preventing HIV infection diseases,which comprises administering the photosensitizing dye.

BACKGROUND ART

Acquired immunodeficiency syndrome (abbreviated as AIDS hereinafter) isnow epidemic worldwide. AIDS is caused by infection with humanimmunodeficiency virus (abbreviated as HIV hereinafter), and therefore,it is rather correct to call it an HIV infection disease. Mere infectionwith HIV does not cause AIDS, and HIV has an asymptomatic period ofseveral months to several years. After the asymptomatic period, HIVstarts to rapidly collapse immune system and causes symptoms such aslymph node enlargement, anorexia, diarrhea, weight loss, fever andlanguor, which are called AIDS-related complex (abbreviated as ARChereinafter). With the weakened immune system, microorganisms such asbacteria, viruses, fungi and protozoa, which are harmless in ordinarycircumstances, start to affect the body seriously and induceopportunistic infection and the like. These infection diseases arecalled AIDS, which develop as the immune system weakens. AIDS refers tothe condition in a terminal stage of HIV infection diseases, where theimmunity is lowered to such a level as to allow development of acquiredimmunodeficiency syndrome. All the symptoms associated with HIVinfection including AIDS are called HIV infection diseases.

Inherently, humans have an immune system as a mechanism for recognizingand eliminating xenobiotics including pathogens. CD4-Positivelymphocytes are well known as the cells that activate immune system.After invading a body, HIV binds to CD4 proteins of CD4-positivelymphocytes and gets into a cell. Since HIV has a reverse transcriptase,it can transcribe its own RNA to DNA and insert the transcribed DNA intothe cell's nucleus DNA. Thus, CD4-positive lymphocytes infected with HIVgradually die while producing the virus, thus resulting in a decrease inthe cells that control the immune system and destruction of the immunesystem. Making the situation more difficult in the case of HIV infectiondiseases, the more the body tries to defend the virus with the immunesystem, the more actively the virus is produced in the infected cells,which in turn produces an opposite effect of decreased CD4-positivelymphocytes.

With regard to HIV infection diseases, many powerful studies have beencarried out to develop clinically effective antiviral agents andvaccines. Examples of medicaments currently under clinical use orclinical trail are a reverse transcriptase inhibitor, absorptioninhibitor, dekaryotheca inhibitor, Tat inhibitor, translation inhibitor,protease inhibitor as virus particle synthesis inhibitor, provirusactivation inhibitor, HIV protease inhibitor and the like.

Of these medicaments, one of the drugs most frequently used isazidothimidine (abbreviated as AZT hereinafter). AZT was approved as ananti-HIV agent, because its administration significantly lowersmortality. However, AZT has side effects including decrease inneutrophiles, anemia, sleeplessness, nausea and headache, and it onlydelays the onset of AIDS. While other therapeutic agents have been alsotried, they have not proved to be basic therapeutic agents.

Considering the immune system, activation of macrophages is extremelyimportant. For example, when bacteria enter a body, macrophagesphagocytize them and become antigen presenting cells while beingactivated. The information from antigen is transmitted from macrophagesto CD4-positive lymphocytes, and further to B-lymphocytes, and theB-lymphocytes produce antibodies. Bacteria bound with antibodies, orimmunocomplexes, are phagocytically digested and specifically eliminatedspeedily by macrophages. At this time, Fc receptors to captureimmunocomplexes appear on activated macrophages, and the macrophagesshow marked increase of phagocytic activity, increased capability ofactive oxygen production to decompose xenobiotics taken in, reinforcedantigen presentation function, and secretion of various cytokines.Ultimately, activated macrophages destroy cancer cells andvirus-infected cells in cooperation with NK cell and the like. It iswell known that immunity is reinforced by activated macrophages in thisway.

DISCLOSURE OF THE INVENTION

As described above, CD4-positive lymphocytes control whole human immunesystem, such as humoral immunity relating to allergy and bacterialinfection, cell-mediated immunity relating to cancer and virus diseases,and activation of macrophage. The onset of AIDS can be explained by thedecrease of CD4-positive lymphocytes that command the human immunesystem. The real cause, nevertheless, is that macrophages are notactivated, and therefore, cell-mediated immunity cannot be activated. Inlower animals without an immune system, phagocyte cells such asmacrophages eliminate xenobiotics. It is considered, therefore, that ifmacrophages can be activated, the functions of cell-mediated immunitycan be improved and virus can be eradicated, even if CD4-positivelymphocytes have decreased.

It is well known that macrophages are activated by macrophageactivators, such as interferon-gamma, produced by the above-mentionedCD4-positive lymphocytes. When CD4-positive lymphocytes decrease,however, the macrophage activators also decrease. Thus, an activatorthat fulfills the decrease should be supplemented. Studies have beendone from these viewpoints, which resulted in the completion of thepresent invention.

It is therefore an object of the present invention to provide a novelmedicament useful for treating or preventing HIV infection diseases.

Another object of the present invention is to define the dose of amedicament useful for treating or preventing HIV infection diseases.

A further object of the present invention is to provide a method fortreating or preventing HIV infection diseases.

In an attempt to solve the above problems, the present inventorsconducted intensive studies and found that, when at least onephotosensitizinq dye, selected from the group consisting of thecompounds represented by formulae (I) and (II), is administered to anHIV-infected subject, the subject shows improvement or cure of thesymptoms of ARC and increase in CD4-positive lymphocytes, thus affordingan effective treatment of HIV infection diseases:

wherein R₁, R₂ and R₃ may be the same or different and each representsalkyl group having 1 to 4 carbon atoms, and X⁻ represents aphysiologically acceptable monovalent anion, preferably a halogen anion,and more preferably an iodide anion,

wherein R₄, R₅ and R₆ may be the same or different and each representsalkyl group having 5 to 10 carbon atoms, preferably linear alkyl grouphaving 7 carbon atoms, and X⁻ represents a physiologically acceptablemonovalent anion, preferably a halogen anion, and more preferably aniodide anion.

Accordingly, the present invention relates to the following.

(1) An anti-HIV infection agent comprising, as an active ingredient, atleast one photosensitizing dye selected from the group consisting of thecompounds represented by the formula (I) and formula (II) (hereinafterto be also referred to as compound (I) and compound (II), respectively):

wherein R₁, R₂ and R₃ may be the same or different and each representsalkyl group having 1 to 4 carbon atoms, and X⁻ represents aphysiologically acceptable monovalent anion, preferably a halogen anion,and more preferably an iodide anion,

wherein R₄, R₅ and R₆ may be the same or different and each representsalkyl group having 5 to 10 carbon atoms, preferably linear alkyl grouphaving 7 carbon atoms, and X⁻ represents a physiologically acceptablemonovalent anion, preferably a halogen anion, and more preferably aniodide anion.

(2) The agent for anti-HIV infection of the above (1), wherein a dailydose of at least one photosensitizing dye selected from the groupconsisting of the compounds (I) and (II) is 2 to 100 μg per kilogram(kg) body weight.

(3) The agent for anti-HIV infection of the above (1), wherein a dailydose of at least one photosensitizing dye selected from the groupconsisting of the compounds (I) and (II) is 5 to 40 μg per kg bodyweight.

(4) The agent for anti-HIV infection of any of the above (1) to (3),which is an agent for oral administration.

(5) The agent for anti-HIV infection of the above (1), wherein X⁻represents a halogen anion.

(6) The agent for anti-HIV infection of the above (1), wherein X⁻represents an iodide anion.

(7) The agent for anti-HIV infection of the above (1), wherein R₁, R₂and R₃ represent ethyl groups; R₄, R₅ and R₆ represent linear alkylgroups having 7 carbon atoms; and X⁻ represents an iodide anion.

(8) A method for treating or preventing HIV infection diseases, whichcomprises administering at least one photosensitizing dye selected fromthe group consisting of the compounds (I) and (II).

(9) The method of the above (8), wherein a daily dose of at least onephotosensitizing dye selected from the group consisting of the compounds(I) and (II) is 2 to 100 μg per kg body weight.

(10) The method of the above (8), wherein a daily dose of at least onephotosensitizing dye selected from the group consisting of the compounds(I) and (II) is 5 to 40 μg per kg body weight.

(11) The method of any of the above (8), (9) and (10), wherein thephotosensitizing dye is orally administered.

(12) The method of the above (8), wherein X⁻ represents a halogen anion.

(13) The method of the above (8), wherein X⁻ represents an iodide anion.

(14) The method of the above (8), wherein R₁, R₂ and R₃ represent ethylgroups; R₄, R₅ and R₆ represent linear alkyl groups having 7 carbonatoms; and X⁻ represents an iodide anion.

(15) Use of at least one photosensitizing dye selected from the groupconsisting of the compounds (I) and (II) for the production of an agentfor anti-HIV infection.

(16) The use of the above (15), wherein a daily dose of at least onephotosensitizing dye selected from the group consisting of the compounds(I) and (II) is 2 to 100 μg per kg body weight.

(17) The use of the above (15), wherein a daily dose of at least onephotosensitizing dye selected from the group consisting of the compounds(I) and (II) is 5 to 40 μg per kg body weight.

(18) The use of any of the above (15), (16) and (17), wherein the agentfor anti-HIV infection is an agent for oral administration.

(19) The use of the above (15), wherein X⁻ represents a halogen anion.

(20) The use of the above (15), wherein X⁻ represents an iodide anion.

(21) The use of the above (15), wherein R₁, R₂ and R₃ represent ethylgroups; R₄, R₅ and R₆ represent linear alkyl groups having 7 carbonatoms; and X⁻ represents an iodide anion.

(22) A pharmaceutical composition for anti-HIV infection, whichcomprises at least one photosensitizing dye selected from the groupconsisting of the compounds (I) and (II), and a pharmaceuticallyacceptable carrier.

(23) The pharmaceutical composition of the above (22), wherein a dailydose of at least one photosensitizing dye selected from the groupconsisting of the compounds (I) and (II) is 2 to 100 μg per kg bodyweight.

(24) The pharmaceutical composition of the above (22), wherein a dailydose of at least one photosensitizing dye selected from the groupconsisting of the compounds (I) and (II) is 5 to 40 μg per kg bodyweight.

(25) The pharmaceutical composition of any of the above (22),

(23) and (24), which is an agent for oral administration.

(26) The pharmaceutical composition of the above (22), wherein X⁻represents a halogen anion.

(27) The pharmaceutical composition of the above (22), wherein X⁻represents an iodide anion.

(28) The pharmaceutical composition of the above (22), wherein R₁, R₂and R₃ represent ethyl groups; R₄, R₅ and R₆ represent linear alkylgroups having 7 carbon atoms; and X⁻ represents an iodide anion.

(29) A commercial package comprising the pharmaceutical composition ofthe above (22) and a written matter associated therewith, the writtenmatter stating that the pharmaceutical composition can be or should beused for treating HIV infection diseases.

The embodiments of the present invention are explained in the following.

Alkyl groups having 1 to 4 carbon atoms at R₁, R₂ and R₃ may be straightor branched, and may be, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl.

Alkyl groups having 5 to 10 carbon atoms at R₄, R₅ and R₆ may bestraight or branched, and may be, for example, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl,which are preferably linear alkyl groups having 7 carbon atoms.

The physiologically acceptable monovalent anion at X⁻ is exemplified byinorganic anion, for example, a halogen anion such as iodide anion,chloride anion, bromide anion and fluoride anion, an alkylsulfuric acidion wherein alkyl is preferably an alkyl group having 1 to 4 carbonatoms, nitric acid ion, and perchloric acid ion; organic sulfonic acidanion such as p-toluenesulfonic acid ion and benzenesulfonic acid ion;organic carboxylic acid anion such as acetic acid ion, propionic acidion and benzoic acid ion; and other organic acid anion such as nicotinicacid ion and orotic acid ion; with preference given to halogen anion,and more preference given to iodide anion.

Preferable examples of the active ingredient used for the agent foranti-HIV infection of the present invention include a compound of theformula (I) wherein R₁, R₂ and R₃ are ethyl groups and X⁻ is an iodideanion, and a compound of the formula (II) wherein R₄, R₅ and R₆ are—(CH₂)₆CH₃ and X⁻ is an iodide anion.

The photosensitizing dyes used as an active ingredient in the presentinvention can be used alone or in combination of two or more thereof.

The photosensitizing dyes used in the present invention are well-knowncompounds and can be produced by a method reported by Kendall, J. D. andMajer, J. R. in “J. Chem. Soc.”, pp. 690 (1948) or a similar methodthereto. The anions can be introduced by a known anion exchange method.A compound of the formula (I), wherein R₁, R₂ and R₃ are ethyl groupsand X⁻ is an iodide anion, (abbreviated as active ingredient Ahereinafter) is disclosed in JP-A-90025/1991, and a compound of theformula (II), wherein R₄, R₅ and R₆ are —(CH₂)₆CH₃ and X⁻ is an iodideanion, (abbreviated as active ingredient B hereinafter) is disclosed inJP-A-90510/1983. These compounds of the formulae (I) and (II) to be usedin the present invention show extremely low toxicity and extremely fewside effects and are highly safe, as disclosed in these publications.For example, LD₅₀ of the active ingredient B by intraperitonealadministration is 54 mg/kg, and the LD₅₀ thereof by oral administrationis 1.5 g/kg. The active ingredient A does not cause any side effectssuch as toxic state even by oral administration at a high concentrationof 4 g/kg. When used for agents for oral administration,photosensitizing dyes do not need to be highly purified, and as long asthe dyes exert a desired anti-HIV infection activity by oraladministration to mammals including humans, no limitation is posed onthe production method, properties or purity of the dyes.

The photosensitizing dyes to be used for the anti-HIV infection agent ofthe present invention are known to have a macrophage activating actionas disclosed in, for example, (1) Cancer Immunology Immunotherapy, 37,157-162 (1993) and (2) J. Photochem. Photobiol. B: Biol., 295-306(1992). It is the finding of the present inventors that an anti-HIVinfection agent containing, as an active ingredient, at least onephotosensitizing dye, selected from the group consisting of thecompounds represented by the formulae (I) and (II), exerts a strikinglysuperior clinical effect against intractable HIV infection diseaseswhere eradication of virus is difficult.

The present inventors first examined an anti-virus activity of theactive ingredients A and B on HIV and found that these compounds had noanti-virus activity to suppress reproduction of HIV. Surprisingly,however, the photosensitizing dye to be used in the present inventionexhibited clinical effects of increased CD4-positive lymphocytes ofpatients infected with HIV and improvement or cure of ARC of patientsinfected with HIV. This means that the anti-HIV infection agent of thepresent invention is expected to suppress the onset of AIDS or prolonglife after the onset. When an anti-HIV infection agent is administeredalong with blood transfusion, the therapeutic effect can be increased.This is considered to be related to the need of GC-globulins in serumfor the activation of macrophages. The activation of macrophages, whichis characteristic of the agent for anti-HIV infection of the presentinvention, is expressed in the presence of lymphocytes (T- andB-lymphocytes) and GC-globulins. Thus, a synergistic effect can beexpected by the agent for anti-HIV infection of the present inventionand blood transfusion employed for regular treatment of AIDS.

The agent for anti-HIV infection of the present invention can beadministered to mammals including humans, monkeys, cattle, cats and thelike.

The agent for anti-HIV infection of the present invention can be usedboth for oral administration and parenteral administration, such asinjection, intrarectal, nasal drop, percutaneous, transmucosal andsublingual administrations. The active ingredient in the presentinvention can be administered in the form of a conventionalpharmaceutical preparation upon mixing with a pharmaceuticallyacceptable nontoxic carrier in a solid or liquid state, which issuitable for an administration route of oral administration, intrarectaladministration, injection administration, nasal drop administration,percutaneous administration, transmucosal administration, sublingualadministration and the like. The oral administration of the agent isparticularly highly effective, and an adequate amount of the activeingredient, which is generally about 2 to 12 μg per kg body weight, intablet or powder may be administered one to several times a daydepending on the disease state. The daily dose of the active ingredient,preferably that by oral administration, is generally 2 to 100 μg per kgbody weight, and preferably 5 to 40 μg per kg body weight. In the caseof oral administration, the agent for anti-HIV infection of the presentinvention is preferably held and dissolved in the mouth on an emptystomach. Although the effective dose varies depending on individualdifference, the dose can be increased or decreased using, as an index,vitality, appetite, sleep, urination, biorhythm, relief fromconstipation, and manifestation of other useful subjective responses ofpatients under medication, because the agent for anti-HIV infection ofthe present invention shows extremely low toxicity, extremely few sideeffects and superior safety. The agent for anti-HIV infection of thepresent invention is also advantageous in that it can control biorhythmof body and affords self-judgment of adequate dose based on subjectivesymptoms.

Examples of the dosage form of the agent for anti-HIV infection of thepresent invention include oral agents such as tablets, pills, powders,granules, capsules, troches and syrups, injections, suppositories,collunariums, preparations for percutaneous administration such asointments, creams and plasters, preparations for transmucosaladministration, sublinguals, atomizers, inhalants and the like.

Examples of the pharmaceutically acceptable carriers include excipientssuch as lactose, corn starch, sucrose, glucose, sorbitol, mannitol,maltose, trehalose, crystalline cellulose, carboxymethylcellulose,calcium carboxymethylcellulose, sodium hydrogencarbonate and dextrin;binders such as methylcellulose, gum arabic, tragacanth gum, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, pullulan and sucrose fatty acid ester; thickeningagents such as sodium carboxymethylcellulose, calciumcalboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose,hydroxypropylmethylcellulose and methylcellulose; lubricants such asmagnesium stearate, calcium stearate, talc and light anhydrous silicicacid; base for suppository such as polyethylene glycol and cacao butter;and inorganic or organic solvents such as distilled water, distilledwater for injection, sterile purified water, physiological saline, plantoils (olive oil, sesami oil, soybean oil, corn oil and peanut oil),glycerin, ethanol and propylene glycol. Furthermore, additives such aspreservatives (e.g., sodium benzoate, benzalkonium chloride,benzethonium chloride, methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate,sorbic acid and potassium sorbate); emulsifiers (e.g., glycerylmonostearate); and pH adjusting agents including buffers (e.g.,hydrochloric acid, citric acid, acetic acid, tartaric acid, sodiumhydrogencarbonate, sodium hydroxide and sodium carbonate) can be addedto the pharmaceutical preparation of the present invention.

The agent for anti-HIV infection of the present invention can be used incombination with other medicaments. Examples of such medicaments includeantiviral agents, antibiotics, analgesic antipyretics, mucous membranepreventive agents, immunostimulants, vitamins, skin protective agentsand the like.

The antiviral agents that can be used in combination with the agent foranti-HIV infection of the present invention are not particularly limitedso far as they are anti-HIV agents usable for the treatment of HIVinfection diseases. Preferable examples of the antiviral agents arenucleoside derivatives such as AZT, dideoxyinosine (ddI),dideoxycytidine (ddC), lamivudine (3TC) and stavudine (d4T); proteaseinhibitors such as indinavir (IDV), saquinavir, ritonavir (RTV) andnelfinavir; and interferons such as interferon-α, interferon-β andinterferon-γ. One or more of these antiviral agents can be used incombination with the agent for anti-HIV infection of the presentinvention.

Examples of the antibiotics usable in combination with the agent foranti-HIV infection of the present invention include antibacterial agentsand antifungal agents including those for andidasis, Pneumocystiscarinii pneumonia and the like.

In the present invention, by the “HIV infection diseases” is meant thecondition of infection with HIV, including AIDS, symptomatic orasymptomatic HIV infection diseases such as ARC, and the like.

In the present invention, by the “agent for anti-HIV infection” is meantmedicaments for prevention and/or treatment of HIV infection diseases.The “treatment” includes that aiming at improvement, alleviation andcure of symptoms. The “treatment of HIV infection diseases” includesthat aiming at improvement, alleviation and cure of symptoms caused byHIV infection, and prevention and delaying of the onset of AIDS.Concrete examples include treatments aiming at increasing or suppressingthe decrease in CD4-positive lymphocytes; increasing or suppressing thedecrease in NK cell activity; prevention, improvement, alleviation orcure of ARC; prevention or delay of the onset of AIDS; prevention,improvement, alleviation or cure of opportunistic infection; andimprovement, alleviation or cure of the symptoms of AIDS. The symptomsof ARC include lymph node enlargement, anorexia, diarrhea, weight loss,fever, languor, eruption, bronchial asthma and the like.

The therapeutic effect achieved by the agent for anti-HIV infection ofthe present invention can be confirmed by improvement or cure of thesymptoms of ARC, particularly by weight gain or suppression of weightloss of patients infected with HIV or by measuring an increase orsuppression of decrease in CD4-positive lymphocytes or increase/decreaseof cellular immune activity (NK cell activity, ratio of T/B) of patientsinfected with HIV.

EXAMPLES

The present invention is described in more detail by the followingpreparation examples, experimental examples and clinical experimentalexamples according to the present invention.

Preparation Example

Formulation 1

Tablet

Ingredient mg/tablet Photosensitizing dye 0.1 Sodium hydrogencarbonate67.0 Gum arabic 0.8 Talc 2.1 Total 70

Two types of tablets were prepared in a conventional manner using theactive ingredient A or B as a photosensitizing dye in the aboveformulation.

Formulation 2

Troche

Ingredient mg/tablet Active ingredient B 0.1 Lactose 79.9 Corn starch62.5 Sucrose fatty acid ester 7.5 Total 150

A troche of the above formulation was prepared in a conventional manner.

Formulation 3

Powder for Injection

Ingredient mg/ampoule photosensitizing dye 0.2 Glucose 49.8 Total 50

Two types of powders for injection were prepared in a conventionalmanner using the active ingredient A or B as a photosensitizing dye inthe above formulation.

Formulation 4

Troche

Ingredient mg/tablet Active ingredient A 0.1 Lactose 79.9 Sodiumhydrcgencarbonate 62.5 Sucrose fatty acid ester 7.5 Total 150

A troche of the above formulation was prepared in a conventional manner.

Experimental Example 1

To examine the effect on HIV infected cell, MT-4 cells (number of cellsat the start of culture 1×10⁴/well), that underwent anti-HIV assay, wereinfected with an HIV (HTLV-IIIB, 200 CCID₅₀/well), cultured at 37° C.for 4 days, and determined for the inhibitory effect on HIV replication,according to the method by Pauels, R. et al., in J. Virol. Methods, 16,171-185 (1987). Suramin was used as a control. Table 1 shows theresults.

TABLE 1 [Inhibition (%) of [Compound] [Concentration (μM)] HIVreplication] Active ingredient B 500 2 100 1 20 2 Active ingredient A500 1 100 2 20 1 Suramin 100 100 20 100 4 10 0.8 2

As is evident from the above results, the active ingredients A and B didnot suppress the replication of HIV at the tested concentrations.

The clinical experiments using the agent for anti-HIV infection of thepresent invention are explained in the following. The clinicalexperiments described below were conducted in Thailand without informingthe patients of the compound names, chemical structures, etc. of thephotosensitizing dyes used as the active ingredient.

Clinical Experiment 1

The agent for anti-HIV infection of the present invention wasadministered to a patient (male, 39 years old) suffering from ARC. Hehad been diagnosed with HIV infection five years before and receivedadministration of AZT/ddI/RTV for 14 months. This patient showed aCD4-positive lymphocyte (abbreviated as CD4 hereinafter) count of121/mm³ and the body weight of 55.6 kg before administration of theagent for anti-HIV infection of the present invention.

This patient, after administration of the agent for anti-HIV infectionof the preset invention of formulation 1 containing the activeingredient A (daily dose of active ingredient A 500 μg) for 8 weeks,showed an increase in the CD4 count to 181/mm³ and in the body weight to56.9 kg. He also showed increased appetite and increased pectoralmuscle.

Subsequently, he was given the agent for anti-HIV infection of thepreset invention of formulation 1 containing the active ingredient A(daily dose of active ingredient A 1000 μg) for 16 weeks and showed anincrease in the CD4 count to 192/mm³ and in the body weight to 57.1 kg.His bronchial asthma, a symptom of ARC, was also cured.

Clinical Experiment 2

Seven patients suffering from ARC or AIDS were given the agent foranti-HIV infection of the present invention of formulation 1 containingthe active ingredient A. Their medical history before treatment was asfollows:

Patient No. 1 (male, 35 years old) had been diagnosed with HIV infection2 years and 4 months before and received administration of AZT/3TC/IDVfor 7 months. He showed a CD4 count of 165/mm³ and the body weight of76.3 kg before administration of the agent for anti-HIV infection of thepresent invention.

Patient No. 2 (male, 42 years old) had been diagnosed with HIV infection3 years and 5 months before and started to receive administration ofAZT/3TC/IDV at once. He showed a CD4 count of 92/mm³ and the body weightof 76.2 kg before the administration of the agent for anti-HIV infectionof the present invention.

Patient No. 3 (male, 32 years old) had been diagnosed with HIV infection1 year and 9 months before and already developed AIDS. He had receivedadministration of AZT/3TC for 21 weeks, and showed a CD4 count of180/mm³ and the body weight of 53.8 kg before the administration of theagent for anti-HIV infection of the present invention.

Patient No. 4 (male, 54 years old) had been diagnosed with HIV infection7 years and 2 months before and received administration of AZT/ddI for 2years and 10 months and additionally of RTV for 1 year and 11 months.This patient showed an increase in the CD4 count in the beginning ofadministration of the anti-HIV agent, but thereafter showed gradualdecrease in the CD4 count to 222/mm³. The body weight was 76 kg beforethe administration of the agent for anti-HIV infection of the presentinvention.

Patient No. 5 (male, 32 years old) had been diagnosed with HIV infection7 years before and showed a CD4 count of 317/mm³ before theadministration of the agent for anti-HIV infection of the presentinvention.

Patient No. 6 (female, 33 years old) had been diagnosed with HIVinfection 4 years and 2 months before and received administration ofAZT/ddI for 1 year and 8 months. She showed a CD4 count of 353/mm³ andthe body weight of 45.6 kg before the administration of the agent foranti-HIV infection of the present invention.

Patient No. 7 (male, 32 years old) had been diagnosed with HIV infection3 years and 4 months before and received administration of AZT/ddI,which had been changed to IDV/d4T/3TC 9 months before. He showed a CD4count of 254/mm³ and the body weight of 58.2 kg before theadministration of the agent for anti-HIV infection of the presentinvention.

Each patient received the administration of the agent for anti-HIVinfection of the preset invention of formulation 1 containing the activeingredient A (daily dose of active ingredient A 500 μg) for 8 weeks, andmost of the patients showed an increase in the CD4 count and in the bodyweight. Along therewith, their appetite increased, rash, one of thesymptoms of ARC, decreased, hemorrhoid was cured, and insomnia wasameliorated. Table 2 shows the results.

TABLE 2 Administration of active ingredient A for 8 weeks (500 μg/day)Patient Change of Improvement Side No. Gender Body weight Change of CD4(Symptoms of ARC etc.) effects 1 Male 76.3 kg→79.4 kg 165→206 Cure ofhemorrhoids None 2 Male 76.2 kg→76 kg    92→102 Decrease of rash None 3Male 53.8 kg→53.3 kg 180→143 None 4 Male   76 kg→73.4 kg 222→270Increased appetite None 5 Male 57.1 kg#→57.6 kg  317→353 Increasedappetite None 6 Female 45.6 kg→46.4 kg 353→358 Amelioration of insomniaNone 7 Male 58.2 kg→59.1 kg 254→330 Increased appetite None “#”: bodyweight at week 4 of administration of active ingredient A.

As is evident from these results, the agent for anti-HIV infection ofthe present invention shows a remarkable effect. The agents offormulations 2 to 4 also showed similar effects.

Industrial Applicability

It is said that 6% of HIV infected patients develop AIDS every year. Thepatients who developed AIDS have extremely weakened cellular immunity,and suffer from complications of opportunistic infections, such asPneumocystis carinii pneumonia, Kaposi sarcoma and brain disorder(dementia), which is ultimately followed by death. In the treatment ofAIDS patients and asymptomatic HIV-infected patients, the agent foranti-HIV infection of the present invention can achieve several effects.one of them is an increase in CD4-positve lymphocytes. Another is cureof AIDS-related complex (ARC). A further effect is increase of appetiteand weight gain. Based on these effects, the agent can prevent or delaythe onset of AIDS and prolong life of HIV-infected patients. While thetreatment of HIV infection diseases inevitably takes a long time, theagent for anti-HIV infection of the present invention is extremelyuseful for the treatment of HIV infection diseases, because it showsextremely low toxicity, extremely few side effects and superior safety.

It is considered that the agent for anti-hiv infection of the presentinvention activates macrophages, thereby to improve biological functionof eliminating xenobiotics, increase CD4-positve lymphocyte count, andcure arc.

What is claimed is:
 1. A method for treating or preventing HIV infectiondiseases, which comprises administering at least one photosensitizingdye selected from the group consisting of compounds represented by theformulae (I) and (II):

wherein R₁, R₂ and R₃ are the same or different and each representsalkyl group having 1 to 4 carbon atoms, and X⁻ represents aphysiologically acceptable monovalent anion,

wherein R₄, R₅ and R₆ are the same or different and each representsalkyl group having 5 to 10 carbon atoms, and X⁻ represents aphysiologically acceptable monovalent anion.
 2. The method of claim 1,wherein said photosensitizing dye is administered in a daily dose of 2to 100 μg per kg body weight.
 3. method of claim 1, wherein saidphotosensitizing dye is administered in a daily dose of 5 to 40 μg perkg body weight.
 4. The method of claim 1, wherein said photosensitizingdye is orally administered.
 5. The method of claim 1, wherein X⁻represents a halogen anion.
 6. The method of claim 1, wherein X⁻represents an iodide anion.
 7. The method of claim 1, wherein R₁, R₂ andR₃ represent ethyl groups; R₄, R₅ and R₆ represent linear alkyl groupshaving 7 carbon atoms; and X⁻ represents an iodide anion.
 8. Apharmaceutical composition comprising an anti-HIV infection effectiveamount of at least one photosensitizing dye represented by the formulaII:

wherein R_(4,) R₅ and R₆ are the same or different and each representsalkyl group having 5 to 10 carbon atoms, and X⁻ represents aphysiologically acceptable monovalent anion, optionally at least onephotosensitizing dye represented by the formula (I):

wherein R₁, R₂ and R₃ are the same or different and each representsalkyl group having 1 to 4 carbon atoms, and X⁻ represents aphysiologically acceptable monovalent anion, and a pharmaceuticallyacceptable carrier.
 9. The pharmaceutical composition of claim 8,wherein the pharmaceutical composition comprises a daily dose of saidphotosensitizing dye of 2 to 100 μg per kg body weight.
 10. Thepharmaceutical composition of claim 8, wherein the pharmaceuticalcomposition comprises a daily dose of said photosensitizing dye of 5 to40 μg per kg body weight.
 11. The pharmaceutical composition of claim 8,which is in a form for oral administration.
 12. The pharmaceuticalcomposition of claim 8, wherein X⁻ represents a halogen anion.
 13. Thepharmaceutical composition of claim 8, wherein X⁻ represents an iodideanion.
 14. The pharmaceutical composition of claim 8, wherein R₁, R₂ andR₃ represent ethyl groups; R₄, R₅ and R₆ represent linear alkyl groupshaving 7 carbon atoms; and X⁻ represents an iodide anion.
 15. method ofclaim 2, wherein said photosensitizing dye is orally administered. 16.The method of claim 3, wherein said photosensitizing dye is orallyadministered.
 17. The pharmaceutical composition of claim 9, which is ina form for oral administration.
 18. The pharmaceutical composition ofclaim 10, which is in a form for oral administration.